Proinflammatory cytokine gene polymorphisms in Behçet's disease

Beh?et's disease (BD) is a chronic, systemic disease, characterized by oral and genital lesions, and ocular inflammation. There is evidence indicating altered levels of proinflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α) in patients with BD. This study involved 150 patients with BD and 140 healthy controls, and investigated the role of proinflammatory cytokine gene polymorphisms in the disease. The frequency of the TNF-α (-238) G/G genotype was significantly higher in the patient group, compared to the controls (p < 0.001), whilst the G/A genotype was significantly lower in the patients with BD (p < 0.001). Patients with BD showed a significant increase in the TNF-α (- 308, - 238) GG haplotype (p < 0.001), whilst there was a significant decrease in the GA haplotype (p < 0.001). The heterozygous, IL-6 (- 174) C/G genotype (p = 0.005), and the IL-6 (- 174, nt565) haplotype CG (p < 0.001), were significantly decreased in the patient group. The increased production of proinflammatory cytokines in BD could be a consequence of specific, cytokine gene polymorphisms. Particular genotypes and haplotypes in TNF-α were over-represented in BD, which may, in turn, predispose individuals to this disease.     

Graves' ophthalmopathy: a review of immunogenetics

Graves' disease (GD) is the most common cause of thyrotoxicosis and often involves the orbits. Graves' ophthalmopathy (GO), also known as Thyroid Eye Disease (TED), can be clinically significant and advance to sight-threatening stages. Our knowledge of the immunogenetic pathophysiology of GO is rapidly expanding. The present review is an attempt to summarize the current state of knowledge on the immunogenetics of GO. First we briefly review the epidemiology and clinical importance of GO, and then we describe in detail the macromolecular pathogenesis and finally immunogenetics of GO. Discrepancies between the results from various reports and the limitations of the available data are discussed. In particular, there is a scarcity of data from non-Asian populations. While several studies have demonstrated significant associations between polymorphisms in certain genes (especially CTLA-4, HLA-DRB-1, and TNF-α), there is a need for studies that investigate the relationship between polymorphisms and both serum and local concentrations of the resulting proteins. A complete understanding of GO susceptibility and pathogenesis has not been yet possible due to a number of important knowledge gaps that need to be filled by future research.     

Cytokine single nucleotide polymorphisms in Iranian populations

Cytokines are important immunomodulatory molecules involved in immune responses against microorganisms; they also have an important role in the setting of immune system disorders. Cytokine single nucleotide polymorphisms have been extensively studied in different, normal populations as well as in association with disease. Cytokine gene polymorphisms are potentially important as genetic predictors of disease susceptibility, clinical outcome, and as a tool for anthropological studies. In this study, samples have been collected from 455 healthy individuals located in different regions of Iran (Tehran, Yazd, Sistan and Balochistan). Allele and genotype frequencies of cytokine SNP, including: IL-1alpha, IL-1beta, IL-1R, IL-1RA, IL-2, IL-4, IL-4RA, IL-6, IL-10, IL-12, TNF-alpha, TGF-beta and IFN-gamma were investigated, using the PCR-SSP method. Allele frequencies in Tehran and Yazd populations were similar, except for TGF-beta. Allele frequencies in Sistani & Baloch populations were similar at all positions, except for IL-1beta at position of -511 and IFN-gamma genes at position UTR5644; there were some differences in allele frequencies comparing these populations with the Yazd population, including: IL-4, IL-6, IL-10, TGF-beta and TNF-alpha. Although some significant differences were observed for some cytokines, it seems that the cytokine gene polymorphism profile of the Iranian population is similar to that of Caucasians, particularly the Italian population.     

Determination of IL-23 receptor gene polymorphism in Iranian patients with ankylosing spondylitis

Introduction

The result of recent genome-wide association studies revealed that, in addition to HLA-B27, a few non-HLA genes are associated with susceptibility to ankylosing spondylitis (AS) in Caucasian populations. According to these studies, IL-23R is one of the genes that is associated with AS. In this study, we evaluated five important single nucleotide polymorphisms (SNPs) of the IL-23R gene which confers susceptibility to AS, and its effects on the severity of the disease in HLA-B27 positive and negative patients and several subtypes of HLA-B27.

Materials and methods

The study population consisted of 294 AS patients and 352 age-, sex-, and ethnicity-matched healthy controls. All patients were examined by rheumatologists, and met modified,NewYork criteria for the disease. Five SNPs (rs1004819, rs11209032, rs1495965, rs11465804, and rs1004819) of the IL-23R gene were genotyped using the Real-Time PCR TaqMan genotyping method.

Results

We found that only rs1004819 has a significant association with AS, and that the remaining four SNP alleles are not associated with AS. Also, there was no association between these five polymorphisms and BASDAI, BASFI, and BASMI indices. Two haplotypes, ACGAT and ACGAG, were found to be associated with the heritability of AS. In addition, two significant, protective diplotypes (D8, \(\frac{{GCGAG}}{{GTGGG}}\); and D9, \(\frac{{ACGAG}}{{GCGAG}}\)) were discovered.

Conclusion

This study supported our previous findings regarding the differences between the genetic patterns of AS in Iranian patients compared with those in other parts of the world.

     

Cytokine single nucleotide polymorphisms in Iranian patients with pulmonary tuberculosis

BACKGROUND: Several genes coding for different cytokines may affect host susceptibility to tuberculosis. METHODS: In the present study, the allele and genotype frequencies of a number polymorphic genes coding for cytokines or cytokine receptors were investigated in Iranian patients with pulmonary tuberculosis (PTB). RESULTS: From the IL-1 cluster, a positive, significant difference was found at position -889, where the T/T genotype was over represented in PTB patients (p = 0.01); a positive, significant increase was found in the IL1R PstI 1970 C/C genotype, where the C allele was over represented in the PTB patients (p = 0.01). A significant negative association at codon 10 TGF-beta, T allele, was shown in our patients and the C allele and C/C genotype were over represented in the PTB patients (P<0.005). For TNF-alpha at position -238, we found a negative association for the G/A genotype and a positive association for the G/G genotype (p = 0.0009). Significant negative associations at position -590 IL-4, T allele and the T/T genotype were shown in our patients (p = 0.0007); also, the C allele and T/C genotype were significantly increased in our patients (P<0.05). With IL-6 at -174, G/G increased and G/C decreased significantly in the patients (P<0.005). CONCLUSION: Pro-inflammatory cytokines such as TNF-alpha and TGF-beta seem to be decreased, and IL-6 increased in PTB patients.     

Association of IL1R polymorphism with HLA-B27 positive in Iranian patients with ankylosing spondylitis

Ankylosing spondylitis (AS) is one of the most common causes of inflammatory arthritis, with an estimated prevalence of 0.1-0.9%. Genetic factors have been strongly implicated in its aetiology, and heritability as assessed by twin studies has been estimated to be >90%. HLA- B27 is almost essential for inheritance of AS; it is not merely sufficient for explaining the pattern of familial recurrence of the disease. This study's purpose is to investigate the association of ankylosing spondylitis with single-nucleotide polymorphisms (SNPs) in the IL-1 family: IL-1a (-889C/T) rs1800587, IL-1b (-511C/T) rs16944, IL-1b (+3962C/T) rs1143634, IL-1R (Pst-1 1970C/T) rs2234650 and IL-1RA (Mspa-1 11100C/T) rs315952. 99 unrelated Iranian AS patients and 217 healthy control subjects were selected. Cytokine typing was performed by the polymerase chain reaction with sequence-specific primers assay. The allele and genotype frequencies of the polymorphisms were determined: The IL1α rs1800587, IL1β rs16944 and IL1β rs1143634 were not significantly associated with AS. Genotype frequencies at IL1R rs2234650 differed between cases and controls (χ(2)=8.85; p=0.01); the IL1R rs2234650 C/T and T/T genotypes were less common in AS patients than controls. The IL1R rs2234650 C/T genotype was inversely associated with AS comparing with the IL1R rs2234650 C/C genotype (OR=0.48; p=0.005). IL1R rs2234650 C/T genotype was less common in patients than controls (OR=0.37; p=0.02).Furthermore IL1R rs2234650 T allele was strongly associated with HLA-B2702 patients rather than HLA-B2705 but was not associated with HLA-B27 negative patients (OR=0.33; p=0.01). Polymorphisms of IL1α rs1800587, IL1β rs16944 and IL1β rs1143634 were not significantly associated with ankylosing spondylitis but inversely in this study IL1R rs2234650 was significantly associated and carriage of T allele in IL1R rs2234650 seems to be protective, while carriage of C allele result in two fold higher risk of developing AS.     

Association of IL-15 and IP-10 Serum Levels with Cytomegalovirus Infection,CMV Viral Load and Cyclosporine Level after Kidney Transplantation

Background:Cytomegalovirus (CMV) infection is the most common complications following kidney transplantation. Natural killer (NK) cells demonstrated critical anti-viral role in controlling and elimination of CMV after transplantation. Interleukin-15 (IL-15) is a pleiotropic cytokine that promotes the activity of NK cells and strengthens the acquired immune system. Also, IP10 (CXCL10) is a chemotactic factor which regulates NK cell recruitment and antiviral immune response. We aimed to determine the correlation between the serum levels of IL-15 and IP-10 cytokines with CMV infection, CMV viral load, and cyclosporine as a major immunosuppressive treatment after transplantation.Methods:Fifty-eight kidney transplant recipient patients without evidence of CMV virus disease before transplantation surgery were included in the study. From the day of transplant surgery, the patients were evaluated based on the presence of CMV Ag pp65, CMV viral load, serum levels of IL-15 & IP-10, Cyclosporine levels (C0 & C2), Glomerular Filtration Rate (GFR), and hematological & biochemical Index, up to 75 days.Results:Comparison analysis of serum levels of IL-15 and IP-10 showed no significant association with CMV infection in kidney transplant recipients. In addition, CMV viral load and cyclosporine levels at C0 and C2 did not affect patients'' IL-15 and IP-10 levels.Conclusion:The levels of IP-10 and IL-15 cytokines are not affected with CMV infection, even if a viral infection occurs in the early days after transplantation or long afterwards. In addition, taking the different levels of cyclosporine did not affect the cytokines levels. Other mechanisms may play a role in maintaining the levels of these cytokines.Key Words: Cytokine, Cytomegalovirus, IP-10, Interleukin-15, Transplantation     

Polymorphism of killer cell immunoglobulin-like receptors (KIR) and their HLA ligands in Graves’ disease

Killer immunoglobulin-like receptors (KIR) play a pivotal role in commencement of both innate and adaptive immunity. Dysregulation of KIRs is associated with an increased risk of autoimmune disorders. This study was designed to assess whether polymorphisms in KIR gene family and their respective HLA class I ligands confer protection or susceptibly to Graves’ disease (GD). Eighty patients with confirmed GD (cases) and 176 healthy unrelated subjects (controls) were recruited. Using a polymerase chain reaction sequence-specific primer directed method (PCR-SSP), presence or absence of KIR genes and their HLA ligands were determined. No significant differences were observed between case and control groups regarding individual KIR gene frequencies (p > 0.05 in all cases). The frequency of group A haplotype (the most common KIR haplotype, encompassing 2DL1/2DL3/3DL1/2DS4/2DP1/3DP1/2DL4/3DL2/3DL3), was not different between individuals with and without GD. Moreover, among all other haplotypes (group Bx), no significant differences regarding distribution of centromeric and telomeric gene clusters were identifiable. Inhibitory/activatory gene contents were also comparable between the two groups. Four models of KIR-HLA interaction (inhibition, activation, unrestrained inhibition, and unrestrained activation) were constructed. No combination proved to confer susceptibility to, or offer protection against GD. It seems that the contribution of KIR gene polymorphism to natural killer cell dysfunction and other autoimmune abnormalities observed in GD is limited.